A Review of Selected Presentations From the 2016 American Society of Hematology Annual Meeting and Exposition December 3-6, 2016, San Diego, California

As a key cytoplasmic component of the B-cell receptor pathway, Bruton tyrosine kin-ase (BTK) plays a critical role in controlling pro-liferation, survival, and differentiation of B-lineage lymphoid cells.1 Ibrutinib is an orally available small molecule that selectively binds to the cysteine 481 residue in the ATP binding domain of BTK, halting kinase activity and inhibiting signaling downstream from the B-cell receptor. Ibrutinib is approved by the US Food and Drug Administration (FDA) as a once-daily treatment for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who are treatment-naive or who have relapsed/refractory disease.2 Results from the phase 1b/2 study PCYC-1102 and the extension study PCYC-1103 demonstrated the efficacy and safety of ibrutinib monotherapy in patients with CLL/SLL, with a manageable safety profile that allows patients to continue on treatment for an extended duration.3-6 Three-year follow-up data yielded an objective response rate (ORR) of 90% and a complete response (CR) rate of 7% in the overall study population while demonstrating durable remissions and improved quality of response over time.

Dr Susan O’Brien presented 5-year follow-up results from the PCYC-1102 and PCYC-1103 trials, including efficacy and safety outcomes in the overall population and in patients with risk factors.7 PCYC-1102 enrolled 31 treatment-naive CLL/SLL patients ages 65 years or older and 101 patients with relapsed or refractory CLL/SLL. The latter group included 24 patients with high-risk disease, defined as disease progression within 24 months of initiating chemoimmunotherapy. In the treatment-naive vs relapsed/refractory cohorts, the median age was 71 vs 64 years, Rai stage III/IV disease was present in 55% vs 57% of patients, and 19% vs 54% had bulky disease, respectively. Cytogenetic abnormalities observed in the 2 cohorts included del(17p) (6% vs 34%), del(11q) (3% vs 35%), trisomy 12 (26% vs 12%), del(13q) (55% vs 47%), and complex karyotype (13% vs 37%). The immunoglobulin heavy chain variable (IgHV) region was unmutated in 48% of the treatment-naive patients vs 78% of the relapsed/refractory patients. In the relapsed/refractory cohort, patients had a median of 4 lines of prior therapy (range, 1-12).

The ORR in the entire study population of 132 patients was 89%, including 14% CRs, 71% partial responses (PRs), and 3% PRs with lymphocytosis. ORR was 87% in the treatment-naive patients vs 89% in the relapsed/refractory patients, including CRs of 29% vs 10%. Among the patients with relapsed/refractory disease, the ORR was 97% in patients with del(11q), 90% in patients with unmutated IgHV, 90% in those with complex karyotype, and 79% in those with del(17p), including CR rates of 9%, 9%, 7%, and 6%, respectively.

At 5 years, the progression-free survival (PFS) rates were 92% in the treatment-naive cohort vs 43% in the relapsed/refractory cohort (Figure 1). Five-year overall survival (OS) rates were 92% vs 57%, respectively. Among the patients with relapsed or refractory disease, patients with mutated IgHV vs unmutated IgHV demonstrated 5-year PFS rates of 53% vs 38% and 5-year OS rates of 66% vs 55%, respectively. However, the Kaplan-Meier curves for both outcomes showed considerable overlap. In the 34 patients with del(17p) at baseline, median PFS was 26 months (Figure 2), and median OS was 57 months. Five-year PFS was 19%, and 5-year OS was 32%. In the 28 patients with del(11q) at baseline, median PFS was 55 months, and median OS was not reached. Five-year PFS was 33%, and 5-year OS
was 61%.

Among patients with a complex karyotype, 90% had relapsed or refractory disease. These patients had received a median of 4 prior therapies. PFS and OS were reduced in this group of patients. For patients without the complex karyotype, 5-year PFS was 69% and OS was 84%, vs 36% and 46% in patients with a complex karyotype. Five-year survival decreased with the number of prior therapies. Five-year PFS was 92% in treatment-naive patients vs 38% in those treated with 4 or more prior therapies. Five-year OS was 92% vs 47%, respectively. Multivariate analysis revealed del(17p) as the only significant predictor of PFS and OS.

Ibrutinib therapy was generally well-tolerated. The rate of adverse events (AEs) of grade 3 or higher decreased over time. In the entire study population, onset of treatment-emergent AEs of grade 3 or greater was highest in the first year of treatment and decreased during subsequent years. The most common AEs of grade 3 or higher were hypertension (26%), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%). The most common nonhematologic AEs were pneumonia and hypertension in previously treated patients vs hypertension and diarrhea in treatment-naive patients.

For the treatment-naive patients vs those with relapsed/refractory disease, the median time on study was 62 months (range, 1-67 months) vs 49 months (range, 1-67 months). In the 2 cohorts, 65% vs 30% of patients remained on therapy, respectively. Discontinuation of study treatment occurred in 20% of patients owing to an AE and in 26% of patients owing to disease progression. The predominant reasons for discontinuing therapy differed in the 2 patient groups, with progressive disease accounting for 3% in the treatment-naive cohort vs 33% in the relapsed/refractory cohort. AEs accounted for 19% vs 21% of discontinuations, respectively.

BTK is critical for cellular survival and for clonal expansion of malignant cells in CLL/SLL.1 BGB-3111 is an irreversible, highly selective, second-generation inhibitor of BTK, with high oral bioavailability and exposure levels.2 In vitro studies have demonstrated comparable binding potency against BTK for ibrutinib and BGB-3111, with IC50 values of 0.34 nM and 0.36 nM, respectively, in the Rec-1 proliferation assay. Moreover, BGB-3111 has greatly improved binding selectivity compared with ibrutinib, showing reduced binding to the epidermal growth factor receptor, interleukin-2–inducible T-cell kinase, Janus kinase 3 (JAK3), HER2/ERBB2, and TEC kinase. The improved binding selectivity is anticipated to correlate with reductions in certain AEs, including diarrhea, bleeding, and atrial fibrillation.

Dr Constantine Tam presented results from the first-in-human clinical trial of BGB-3111.3 The phase 1 trial included a dose-escalation component followed by expansion. Patients with relapsed or refractory B-cell malignancies according to World Health Organization criteria were enrolled into cohorts for treatment with BGB-3111 dosed once daily at 40 mg, 80 mg, 160 mg, or 320 mg or dosed twice daily at 160 mg, using a modified 3+3 dose escalation design and disease-specific expansion cohorts. Patients with relapsed or refractory B-cell malignancies were assigned to BGB-3111 at 160 mg twice daily or 320 mg once daily for pharmacodynamic assessments. In order to assess BTK occupancy in the lymph nodes at the time of trough drug exposure, paired lymph node biopsies were taken from these patients at baseline and prior to dosing on day 3. BGB-3111 exposure increased in a dose-dependent manner from 40 mg to 320 mg daily. The maximum concentration and area under the curve of BGB-3111 in patients treated with 80 mg daily were similar to those observed in patients treated with ibrutinib dosed at 560 mg daily.4 Free drug exposure from BGB-3111 (40 mg daily) was similar to that observed from ibrutinib (560 mg daily). In cohorts receiving the 2 highest doses of BGB-3111, drug exposure levels were approximately 8-fold higher compared with ibrutinib (560 mg daily). Complete BTK occupancy was observed in peripheral blood mononuclear cells in the lowest dose cohort. Twenty patients with relapsed or refractory B-cell malignancies were enrolled in the pharmacodynamic assessment cohorts. The median trough BTK occupancy in the lymph nodes was 100% in patients receiving BGB-3111 at 160 mg twice daily vs 94% in those receiving 320 mg once daily (P=.002), and the proportion of patients with greater than 90% trough occupancy at all time points was 94% vs 58%, respectively.

Among the 63 enrolled patients with CLL/SLL, 17 had less than 12 weeks of follow-up and were therefore not included in the analysis. One patient discontinued treatment owing to an AE. Sixty-two patients remained on the study with no evidence of progressive disease. The 46 patients had a median age of 67 years (range, 24-79 years), and the median follow-up was 8.6 months (range, 2.2-20.9 months). Nine patients were treatment-naive. The 37 patients with relapsed or refractory disease had received a median of 2 prior therapies (range, 1-6). Molecular risk factors included del(17p)/TP53 mutation (18%), del(11q) (35%), and unmutated IgHV (75%).

The ORR was 96%, including 67% PRs and 28% PRs with lymphocytosis. In the 17 patients with del(17p) and/or del(11q), the ORR was 100%. The overall study group showed a dramatic reduction in lymph node burden by the first scan, which was administered 3 months after treatment was initiated. The median absolute lymph node count peaked at approximately 8 weeks after initiating treatment and returned to baseline after approximately 3 to 4 months. In anemic patients, median hemoglobin levels increased over time, from approximately 9 g/dL at baseline to approximately 15 g/dL by week 60 (Figure 3). Similarly, in patients with a platelet count of less than 100,000/µL at baseline, the median platelet count improved over time.

The most common AE of any grade was bleeding (48%), followed by upper respiratory tract infection (33%) and fatigue (28%). Sixteen patients (35%) had at least 1 AE of grade 3 or greater, 10 patients (22%) had at least 1 serious AE, and 1 patient (2%) discontinued treatment owing to an AE. Diarrhea, bleeding, and atrial fibrillation are known AEs associated with ibrutinib therapy. In the current analysis of 46 patients, 9 patients (20%) experienced diarrhea; all episodes were grade 1 or 2 in severity. One patient (2%) experienced grade 3/4 hemorrhage and 1 patient (2%) experienced atrial fibrillation.

Toxicity restricts chemotherapy regimens to a finite number of treatment cycles. In contrast, ibrutinib is associated with reduced toxicity and therefore is administered until disease progresses or unacceptable toxicity does occur. An integrated safety analysis was undertaken to evaluate the safety and tolerability of ibrutinib therapy in patients with relapsed or refractory CLL/SLL from 2 randomized phase 3 trials: RESONATE (PCYC-1112; A Phase 3 Study of Ibrutinib [PCI-32765] Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia) and RESONATE-2 (PCYC-1115; A Multicenter, Open-Label, Phase 3 Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib Versus Chlorambucil in Patients 65 Years or Older With Treatment-Naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma).1-3 The RESONATE trial included 391 previously treated patients. The treatment arms were ibrutinib at 420 mg once daily (n=195) and ofatumumab at an initial dose of 300 mg followed by 2000 mg via 11 doses given throughout 24 weeks (n=196). In the ofatumumab arm, 132 patients crossed over to ibrutinib following disease progression. RESONATE-2 included 269 treatment-naive patients ages 65 years or older. The treatment arms were ibrutinib at 420 mg once daily (n=136) and chlorambucil at 0.5 mg/kg on days 1 and 15 in a 28-day cycle for a maximum of 12 cycles, with optional dose increases to a maximum of 0.8 mg/kg (n=133).

The integrated analysis included 330 patients who received ibrutinib treatment in RESONATE or RESONATE-2. Two-thirds of patients were male, 51% of patients had Rai stage III/IV disease at baseline, and 54% had bulky disease with a tumor measurement of at least 5 cm. Fifty-nine percent of patients had baseline cytopenias. Patients received ibrutinib for a median of 29.0 months (range, 0.2-42.9 months), and 16% of patients continued treatment for longer than 36 months. Concomitant treatments included CYP3 inhibitors (53%), antiplatelet agents (50%), anticoagulants (28%), packed red blood cell transfusions (6%), granulocyte growth factors (3%), and intravenous immunoglobulin (2%). Among the 38% of patients who discontinued treatment, the most common reasons were progressive disease (16%), AEs (11%), or death (5%). Discontinuations owing to an AE occurred in 19% of patients overall, and were highest in the first year of treatment, with 20, 10, and 7 discontinuations during years 1, 2, and 3, respectively. Similarly, dose reductions owing to an AE occurred in 13% of patients and were highest during the first year of treatment, with reductions reported in 23, 16, and 5 patients during years 1, 2, and 3, respectively.

The most common AEs of any grade were diarrhea (53%) and fatigue (36%; Figure 4). Other AEs of any grade reported in at least 25% of patients were upper respiratory tract infection (30%), nausea (29%), pyrexia (28%), and anemia (27%). Grade 3/4 AEs observed in at least 5% of patients included neutropenia (18%), pneumonia (12%), anemia (7%), and hypertension (6%). AEs leading to dose reduction in at least 3 patients included neutropenia and diarrhea, each occurring in 5 patients; atrial fibrillation, occurring in 4 patients; and anemia, thrombocytopenia, and arthralgia, each occurring in 3 patients. AEs leading to discontinuation in 2 or more patients included pneumonia in 4 patients, anemia and atrial fibrillation in 3 patients each, and diarrhea, subdural hematoma, and thrombocytopenia, each occurring in 2 patients. Of the 29 patients (9%) who died, the most common reason was progressive disease, reported in 8 patients, followed by pneumonia/lung infection, reported in 7 patients. AEs of particular clinical relevance included diarrhea, arthralgia, hypertension, rash, bleeding or bruising, fatigue, and atrial fibrillation. The majority of these AEs were of grade 1 or 2, and most resolved, with the exception of hypertension, which resolved in only 37% of cases. The median duration of these AEs was less than 35 days, with the exception of fatigue, which had a median of duration of 57 days. Rates of diarrhea, fatigue, rash, and grade 3/4 infections were highest during the first year of ibrutinib treatment, while rates of arthralgia and atrial fibrillation remained similar during years 1, 2, and 3 of treatment. In contrast, rates of hypertension increased with continued treatment; however, the majority of hypertensive events were ongoing or recurrent after 1 year of treatment.

In the same study, a long-term safety analysis was conducted on patients from the PCYC-1102 and PCYC-1103 trials who received ibrutinib therapy.3 The 94 patients from these trials had a median follow-up of 47.9 months (range, 0.3-67.4 months). The most common grade 3/4 hematologic AEs were neutropenia (15%), thrombocytopenia (7%), and decreased lymphocyte count (6%). The most common grade 3/4 nonhematologic AEs were hypertension (30%), pneumonia (17%), and atrial fibrillation (11%). Reported secondary malignancies included basal cell carcinoma and squamous cell carcinoma in 4 patients each, and myelodysplastic syndrome in 2 patients.

Ibrutinib may be associated with AEs such as diarrhea, rash, atrial fibrillation, and bleeding, which may result from off-target effects.1 Acalabrutinib (ACP-196) is a potent, second-generation inhibitor of BTK that binds irreversibly to the BTK kinase domain but has shown minimal activation of nontarget receptor pathways.2,3 In kinase inhibition assays, the IC50 of acalabrutinib is greater than that of ibrutinib when tested against TEC (93 nM vs 7.0 nM), epidermal growth factor receptor (>1000 nM vs 5.3 nM), HER2/ERBB2 (~1000 nM vs 6.4 nM), interleukin-2–inducible T-cell kinase (>1000 nM vs 4.9 nM), and others. Dr Farrukh Awan presented results from the ibrutinib-intolerant patients enrolled in the ongoing, multinational phase 1/2 ACE-CL-001 trial, which investigated acalabrutinib monotherapy in patients with CLL/SLL.4 Results have already been reported for the cohort of 60 patients with relapsed or refractory disease, showing an ORR of 95%, including 85% PRs and 10% PRs with lymphocytosis.2 In addition, results from 72 treatment-naive patients yielded an ORR of 97%, including 87.5% PRs and 10% PRs with lymphocytosis.

The ibrutinib-intolerant cohort included adults with confirmed CLL who were intolerant to ibrutinib as determined by the investigator. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Patients were excluded if their CLL involved the central nervous system or if they had significant cardiovascular disease. Thirty patients received acalabrutinib at 100 mg twice daily and 3 received acalabrutinib at 200 mg daily. The data cutoff was September 1, 2016. The primary objective was safety, including frequency, severity, and attribution of AEs, with secondary objectives of ORR, duration of response, and PFS. The 33 enrolled patients had a median age of 64 years (range, 50-82 years), and 61% were male. Thirty-one percent of patients had Rai stage III/IV disease, and 78% had bulky disease with a tumor diameter of at least 5 cm. Patients had received a median of 4 prior therapies (range, 2-13). Most patients (91%) had received ibrutinib as their most recent prior therapy, and the median duration of prior ibrutinib treatment was 11.5 months (range, 1-62 months). Baseline cytopenias were present in 78% of patients. Genomic risk factors included del(11q), del(17p), and unmutated IgHV in 31%, 38%, and 81% of patients, respectively. The most common AEs of any grade reported during ibrutinib treatment included rash (21%), arthralgia (18%), diarrhea (12%), and fatigue (12%).

The median time on acalabrutinib was 12.2 months (range, 0.2-23.6 months). Twenty-four patients (73%) remained on acalabrutinib therapy. Reasons for discontinuation included progressive disease (9%), AEs (9%), and physician decision (3%). AEs leading to discontinuation included 1 patient with hemorrhagic stroke resulting in death, 1 patient with fungal infection leading to death, and 1 patient who was diagnosed with metastatic endometrial cancer. Twelve patients (36%) had previously experienced an AE with ibrutinib that recurred during treatment with acalabrutinib. Only 2 of these events increased in severity, rising from grade 1 to grade 2. No patients discontinued acalabrutinib owing to a previous ibrutinib-related AE.

The most common AEs of any grade in the 33 patients treated with acalabrutinib included diarrhea (52%), headache (39%), cough (24%), and increased weight (24%). Grade 3/4 AEs occurring in at least 2 patients included thrombocytopenia in 9% of patients, and anemia, neutropenia, pneumonia, hypertension, and paresthesia, each occurring in 6% of patients. Serious AEs occurred in 11 patients (33%). Two atrial fibrillation events were reported: 1 grade 2 and 1 grade 3. Both were considered unrelated to study drug by the investigator. The 2 grade 5 events included 1 each of hemorrhagic stroke and disseminated systemic fungal infection, and these were also considered unrelated to study drug by the investigators.

In the 29 patients evaluable for a response, the ORR was 79.3% (95% CI, 60.3%-92.0%), including 1 patient (3.4%) with a CR, 15 (51.7%) with a PR, and 7 (24.1%) with a PR with lymphocytosis (Table 1). The median time until achievement of PR with lymphocytosis or better was 1.9 months, and response duration was at least 12 months in 81% of responding patients. Median PFS was not yet reached. An ongoing phase 2 study (A Study of ACP-196 [Acalabrutinib] in Subjects With Relapsed/Refractory CLL and Intolerant of Ibrutinib Therapy) is evaluating acalabrutinib monotherapy in patients with relapsed refractory CLL and ibrutinib intolerance.5

Because CLL/SLL occurs predominantly in the elderly, the patient population is marked by increased comorbidities that limit the aggressiveness of treatment. Ibrutinib is associated with favorable tolerability and enables treatment without chemotherapy. Dr Paul Barr presented updated efficacy and safety data from the phase 3 RESONATE-2 trial, which evaluated first-line ibrutinib vs chlorambucil in elderly patients with CLL/SLL.1,2 The study enrolled 269 patients ages 65 years or older with treatment-naive CLL/SLL who were not candidates for fludarabine-based therapy. Patients with del(17p) were ineligible. After stratification for performance status and disease stage, patients were randomly assigned to receive ibrutinib at 420 mg once daily until disease progression or unacceptable toxicity, or chlorambucil at 0.5 mg/kg up to a maximum of 0.8 mg/kg on days 1 and 15 in 28-day cycles for a maximum of 12 cycles until disease progression, unacceptable toxicity, or lack of efficacy. Patients with progressive disease were enrolled in a separate extension study (PCYC-1116-CA) with treatment based on investigator choice. The updated analysis of data from 269 patients therefore included 55 patients from the chlorambucil arm who experienced disease progression and underwent subsequent treatment with ibrutinib.

The 269 patients had a median age of 73 years (range, 65-90 years), and 45% had Rai stage III/IV disease. Thirty-five percent of patients had bulky disease, with a tumor diameter of 5 cm or greater, and 57% had an ECOG performance status of 1 or 2. Del(11q) was observed in 20% of patients, and unmutated IgHV in 44%. Comorbidities included a Cumulative Illness Rating Scale for Geriatrics score of greater than 6 in 32%, creatinine clearance of less than 60 mL/min in 47%, hemoglobin level of 11 g/dL or lower in 39%, and platelet count of 100 × 109/L or lower in 24% of patients. After 29 months of follow-up, the PFS was significantly improved in patients treated with ibrutinib (89 months vs 34 months; hazard ratio [HR], 0.121; 95% CI, 0.074-0.198; P<.0001). In the subgroup of patients with del(11q), ibrutinib treatment was associated with a 99% reduction in the risk of progression or death compared with chlorambucil (HR, 0.014; 95% CI, 0.002-0.108; P<.001; Figure 5). In patients without del(11q), ibrutinib conferred an 82% reduction in the risk of progression or death vs chlorambucil (HR, 0.180; 95% CI, 0.106-0.303; P<.0001). Ibrutinib treatment was associated with a 92% risk reduction in patients with unmutated IgHV (P<.0001) and an 83% risk reduction in patients with mutated IgHV (P<.001).

For the entire study population, 24-month OS was 95% with ibrutinib vs 84% with chlorambucil. These results confirmed the original findings that yielded an estimated 24-month PFS of 98% with ibrutinib vs 85% with chlorambucil, and a risk reduction of 84% with ibrutinib compared with chlorambucil (P=.001).1 The 136 patients in the ibrutinib arm had an ORR of 92%, including 18% CRs or CRs with incomplete blood count recovery; 1% nodular PRs, indicating persistent nodules in the bone marrow; 71% PRs; and 1% PRs with lymphocytosis. CR rates improved with continued ibrutinib treatment, increasing from 7% at 12 months of follow-up, to 15% at 24 months, to 18% at 29 months. The ORR was 100% in patients with del(11q) vs 90% in those without, and 95% in patients with unmutated IgHV vs 88% in those without. With ibrutinib treatment, sustained improvement in the hemoglobin level was achieved in 90% of anemic patients vs 45% with chlorambucil (P<.0001). In patients with thrombocytopenia, a sustained improvement in platelet levels was achieved in 80% of those treated with ibrutinib vs 46% of those treated with chlorambucil (P=.0055).

The median duration of ibrutinib treatment was 29 months (range, 1-36 months), and 79% of patients were continuing treatment with ibrutinib at the time the study was reported. Among the 21% of patients who discontinued treatment, the reasons included AEs (12%), death (4%), disease progression (3%), and withdrawal of consent (1%). In patients treated with ibrutinib, the most common AEs of any grade included diarrhea (45%), fatigue (33%), and cough (28%). Anemia, nausea, peripheral edema, arthralgia, and pyrexia of any grade were observed in 20% to 23% of patients. Among patients treated with ibrutinib, major hemorrhage occurred in 7% and atrial fibrillation in 10%. During the 29 months of follow-up, AEs of grade 3 or greater included neutropenia (12%), pneumonia (7%), anemia (7%), hypertension (5%), hyponatremia (4%), and atrial fibrillation (4%). The majority of treatment-emergent AEs of grade 3 or greater occurred during the first year of treatment. However, atrial fibrillation of grade 3 or greater was reported in 1% of patients during the first year of treatment with ibrutinib and in 4% of patients during the third year of treatment. Rates of dose reduction and discontinuation owing to an AE also decreased over time.

Updated Analysis of Overall Survival in Randomized Phase III Study of Idelalisib in Combination With Bendamustine and Rituximab in Patients With Relapsed/Refractory CLL

The treatment landscape for patients with relapsed or refractory CLL remains limited. Idelalisib is a selective, orally available, first-in-class, reversible inhibitor of phosphatidylinositol-4,5-bisphosphate 3-kinase delta (PI3Kδ) and represents an alternative to ibrutinib for disrupting B-cell receptor–mediated signal transduction. The PI3K family of enzymes mediates numerous cellular functions, including growth, motility, homing, retention, and adhesion. In the B-cell receptor pathway, PI3Kδ controls survival, proliferation, and chemokine secretion and is constitutively overexpressed in the B cells of CLL patients. Early experiments demonstrated the ability of idelalisib to induce apoptosis in primary CLL cells ex vivo while retaining activity in the presence of stromal cells.1 It is approved in combination with rituximab for the treatment of relapsed CLL in patients ineligible for rituximab monotherapy based on comorbidities.2

Dr Andrew Zelenetz presented updated results from GS-US-312-0115 (A Randomized, Double-Blind and Placebo-Controlled Study of Idel-alisib in Combination With Bendamustine and Rituximab for Previously Treated Chronic Lymphocytic Leukemia [CLL]), which examined the addition of idelalisib to bendamustine plus rituximab.3,4 The randomized, placebo-controlled, double-blind, phase 3 study enrolled adult CLL patients whose prior therapy included a purine analogue, bendamustine, or an anti-CD20 antibody and whose disease progressed within 36 months of completion of the last prior therapy. Among patients previously treated with bendamustine, this therapy ended at least 6 months before study enrollment. Patients with disease refractory to bendamustine were ineligible.

All patients received bendamustine at 70 mg/m2 on days 1 and 2 and rituximab at 375 mg/m2 on day 1 of cycle 1 followed by 500 mg/m2 on day 1 of cycles 2 through 6. In addition to this regimen, patients were randomly assigned to receive idelalisib at 150 mg twice daily or placebo. Treatment with idelalisib or placebo was continued until disease progression, intolerable toxicity, withdrawal of consent, or death. Stratification factors included del(17p) and/or TP53 mutation, IgHV mutation, and relapsed or refractory disease. The primary endpoint was PFS, with secondary endpoints of ORR, nodal response, OS, and CR.

The baseline characteristics were well-balanced between the 2 arms. The original study population of 416 patients had a median age of 63 years (range, 32-83 years), and 76% were male. Forty-five percent of patients had Rai stage III/IV disease. Patients had a median of 2 prior treatment regimens (range, 1-13), and the most common prior regimens were fludarabine, cyclophosphamide, and rituximab (67%), fludarabine and cyclophosphamide (22%), and chlorambucil (18%). More patients in the idelalisib arm had received prior bendamustine (15% vs 8%). Thirty-three percent of patients had del(17p) or TP53 mutation, 83% had unmutated IgHV, and one-third had refractory disease.

After a median of 21 months of follow-up, more patients remained on study in the idelalisib arm (34%) than the placebo arm (11%), and 31% vs 0 patients continued on study treatment, respectively. After the initial prespecified interim analysis, patients in the placebo arm were informed and discontinued treatment. The updated analysis demonstrated a significant improvement in survival with idela-lisib, with a median OS of not reached vs 40.6 months for placebo (HR, 0.67; 95% CI, 0.47-0.96; P=.04). PFS based on independent review was also significantly improved with idelalisib (23.0 months vs 11.1 months; HR, 0.31; 95% CI, 0.24-0.41; P<.0001). In the subgroup of patients without del(17p) or TP53 mutation, the median PFS was 27.8 months in the idelalisib arm vs 11.2 months in the placebo arm (HR, 0.25; 95% CI, 0.17-0.35; P<.001). Further subgroup analysis favored the inclusion of idelalisib, although many of these subgroups included few patients.

Concerns have been raised regarding rates of infection in patients treated with idelalisib. Infection with Pneumocystis jirovecii pneumonia was observed in 4 patients (2%) in the idel-alisib arm vs 0 patients in the placebo arm, and cytomegalovirus infection was observed in 13 patients (6%) vs 3 (1%), respectively. However, the only death from these infections occurred in a patient with cytomegalovirus infection in the placebo arm. The risk of cytomegalovirus infection decreased over time in both arms. Grade 3/4 alanine or aspartate transaminase elevations were more common in patients treated with idelalisib (21% vs 3% and 16% vs 3%, respectively).

CLL2-BIG – A Novel Treatment Regimen of Bendamustine Followed By GA101 and Ibrutinib Followed by Ibrutinib and GA101 Maintenance in Patients With Chronic Lymphocytic Leukemia (CLL): Results of a Phase II-Trial

Obinutuzumab (GA101) is a humanized, glycoengineered, anti-CD20 antibody. In preclinical studies, obinutuzumab was superior to rituximab in the ability to induce direct cell death and antibody-dependent cellular cytotoxicity, with reduced dependency on complement.1 In a phase 3 trial of 781 patients, the combination of chlorambucil plus an anti-CD20 antibody was superior to chlorambucil alone in CLL patients with comorbidities.2 Dr Julia von Tresckow presented results from the CLL2-BIG (Sequential Regimen of Bendamustine [B] Followed by GA101 and Ibrutinib [I] in CLL Patients) trial.3 The prospective, open-label, multicenter, phase 2 trial investigated sequential treatment with bendamustine for initial debulking followed by induction and maintenance treatment with obinutuzumab and ibrutinib. A high tumor burden was defined by an absolute lymphocyte count greater than 25,000 cells/µL and/or lymph node measurement of 5 cm or greater, and these patients received 2 cycles of bendamustine at 70 mg/m2 on days 1 and 2 prior to induction. Patients received 6 cycles of induction treatment with obinutuzumab and ibrutinib, followed by maintenance therapy with ibrutinib and obinutuzumab every 3 months for up to 24 months or until they achieved a CR (as shown by absence of minimal residual disease). Two cycles of debulking with bendamustine were given before the start of the induction period in patients with an initial high tumor burden. The primary endpoint is the ORR 3 months after the start of the last induction cycle. Secondary endpoints included the ORR after debulking, minimal residual disease, and safety.

Sixty-six patients were enrolled between January 2015 and August 2015. Five patients completed fewer than 2 induction cycles and were excluded from the analysis. The 61 patients included in the analysis had a median age of 66 years (range, 36-83 years), with 51% of patients older than 65 years. Thirty patients were treatment-naive, and 31 had relapsed or refractory CLL. All patients had an ECOG performance status of 0 or 1. Fifty-seven percent of patients were male, and the median time from initial diagnosis was 56.5 months (range, 1.2-222.8 months). Patients had Binet stage A (26.2%), B (37.7%), or C (36.1%) disease, and the median Cumulative Illness Rating Scale score was 3 (range, 0-11). The median creatinine clearance rate was 76.5 mL/min (range, 33.1-154.7 mL/min). The genetic risk factors unmutated IgHV, del(11q), and del(17p) were present in 70.0%, 23.0%, and 13.1% of patients, respectively. Other genetic risk factors included del(13q) in 50.8% of patients, trisomy 12 in 19.7% of patients, and TP53 deletion in 19.7% of patients.

Forty-four patients underwent debulking with bendamustine, including 27 treatment-naive patients and 17 with relapsed or refractory disease. Bendamustine yielded an ORR of 65.9%, including 4 patients (9.1%) with an unconfirmed CR, 3 (6.8%) with an unconfirmed CR with incomplete bone marrow recovery, and 22 (50.0%) with a PR (Table 2). Among the 61 patients who underwent induction treatment, 1 patient with a documented PR died after the fifth treatment course owing to duodenitis/defense weakness related to study therapy. The ORR in 61 patients was 100% by investigator assessment, including unconfirmed CRs in 25 (41%), unconfirmed CRs with incomplete bone marrow recovery in 3 (4.9%), and PRs in 33 (54.1%). Based on flow cytometry analysis of peripheral blood, 29 patients (47.5%) achieved negative minimal residual disease at final restaging, including 19 patients with an unconfirmed CR, 1 patient with an unconfirmed CR and incomplete bone marrow recovery, and 9 patients with a PR. The most common grade 3/4 AEs included neutropenia (14.8%), thrombocytopenia (13.1%), infusion-related reactions (4.8%), and pneumonia (3.3%).

The 2016 American Society of Hematology (ASH) Annual Meeting featured several important abstracts on chronic lymphocytic leukemia (CLL). Long-term follow-up analyses were presented for clinical trials of ibrutinib. Other studies examined BGB-3111, a new Bruton tyrosine kinase (BTK) inhibitor, and idelalisib in combination with bendamustine and rituximab.

Ibrutinib

I presented an analysis of the 5-year experience with ibrutinib.1 These data are important because they represent the longest follow-up available for ibrutinib. The analysis was based on data from the original phase 1b/2 study, which included 2 cohorts: 31 previously untreated patients ages 65 years or older, and 101 patients with relapsed/refractory disease, who had received a median of 4 prior therapies.2 The relapsed/refractory patients were therefore heavily pretreated. The follow-up analysis shows a best response of 89% for both groups together. In the treatment-naive patients, the complete response (CR) rate was 29%, which reflects a slight improvement from the 26% that was reported for this group in 2015.

This 5-year analysis provided several new findings concerning progression-free survival (PFS). In previous studies of ibrutinib, the median PFS had not been reached for all patients. The only subgroup with a median PFS had been relapsed/refractory patients with del(17p), in whom it was 26 months. A new finding from the 5-year data is a median PFS of 52 months in the overall relapsed/refractory setting. The median PFS for patients with the del(11q) is 55 months. Among patients who do not have either of these high-risk abnormalities—del(17p) or del(11q)—the median PFS has still not been reached, which is quite striking at 5 years, especially given that the median number of prior regimens in these patients was 4. Median overall survival was reached in only one group of patients, relapsed/refractory patients with del(17p), in whom it was 57 months.

Among treatment-naive patients, the survival curve had been very similar for years. There had been 1 early drop in the curve, which reflected a patient who progressed and died within the first year of the study. The 5-year analysis shows another late drop in the curve just before 5 years, which represents a patient in remission who died of a secondary malignancy. Among the original 31 treatment-naive patients, only a couple have come off study. Only 1 patient has progressed. The 5-year PFS in the treatment-naive cohort is 96%. These data are very striking.

An analysis was performed to identify any factors that might predict overall survival or PFS and included previous lines of prior therapy and complex karyotype. A multivariate analysis of the relapsed/refractory patients showed that the relevant predictor was the del(17p), which shortened both PFS and overall survival.

Dr Paul Barr presented updated efficacy and safety data from the phase 3 RESONATE-2 trial (PCYC-1115; A Multicenter, Open-Label, Phase 3 Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib Versus Chlorambucil in Patients 65 Years or Older With Treatment-Naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma).3,4 This randomized trial led to the approval of ibrutinib as frontline therapy in the United States. Patients were randomly assigned to receive the standard dose of ibrutinib, 420 mg daily, or chlorambucil. Patients were older than 70 years, or ages 65 to 70 years with comorbidities; their median age was 72 years. Chlorambucil was a reasonable comparator arm in this older population. The results, as reported in 2015 in the New England Journal of Medicine, showed that PFS was dramatically longer with ibrutinib than with chlorambucil.4 The updated data presented by Dr Barr continued to show a dramatic difference. Median PFS was not yet reached with ibrutinib vs 15 months with chlorambucil. The 24-month PFS was 89% with ibrutinib. Even though crossover was allowed on this trial, there was still a survival advantage in the ibrutinib arm.

A subset analysis evaluated the impact of del(11q) and mutated vs unmutated immunoglobulin heavy chain variable (IgHV). The relevance of this analysis is not focused on response. It is known that with chemotherapy-based regimens, response rates are similar regardless of whether patients have del(11q) or unmutated IgHV. Progression-free survival, however, is significantly shorter in patients with del(11q) or unmutated IgHV. This difference was seen in the chlorambucil arm in this study. Among patients treated with chlorambucil, those with the del(11q) had a shorter PFS than those without del(11q). Similarly, patients with unmutated IgHV had a shorter PFS than those without the mutation when treated with chlorambucil. These differences were not seen in the ibrutinib cohort. The entire ibrutinib cohort had a high response rate of 92%. In addition, the CR rate increased from 7% at 1 year to 18% at 2 years. Based on the phase 2 data, the CR rate could potentially improve with time.

The adverse events (AEs) reported for ibrutinib were as expected. Even though the population was older, 16 patients (approximately 12%) discontinued treatment owing to AEs. It is good to know that the longer follow-up is showing robust data with ibrutinib in the frontline setting.

When interpreting these results, some physicians might mention that the current standard of care is to use chlorambucil plus an antibody, rather than chlorambucil alone. However, the median PFS was only 26 months in the randomized trial that led the US Food and Drug Administration (FDA) to approve obinutuzumab with chlorambucil as a frontline regimen,5 which is far shorter than that achieved with ibrutinib. Therefore, the results of RESONATE-2 are not negated by the use of chlorambucil without an antibody.

BGB-3111

BGB-3111, a new oral agent, is a BTK inhibitor. It is very potent against BTK and has higher IC50 for some of the other kinases that ibrutinib targets. For example, it has a higher IC50 for the epidermal growth factor receptor (EGFR), which could theoretically translate into less likelihood of rash or diarrhea compared to that seen with other BTK inhibitors. It has a much higher IC50 for IL2 inducible T-cell kinase (ITK) than ibrutinib, so potentially it will not interfere with the activities of antibodies. The IC50 on TEC, however, appears similar between BGB-3111 and ibrutinib, which is important because TEC may be responsible for the atrial fibrillation and bleeding that can be seen with ibrutinib. It would be ideal to have a BTK inhibitor that does not target TEC, such as the novel agent acalabrutinib.6

Dr Constantine Tam presented interim results of an ongoing phase 1 study of BGB-3111.7 The study evaluated a variety of different doses ranging from 40 mg daily to 160 twice daily. The study showed that higher plasma levels are achieved with the standard dose of BGB-3111, and they were associated with activity. An interesting aspect of this study is that it looked within the lymph nodes to determine BTK occupancy. The optimal dose of ibrutinib, 420 mg daily, was selected because it resulted in almost complete occupancy of BTK in the peripheral blood mononuclear cells. The lymph nodes, however, were not evaluated when determining this dose. This information might be relevant because there are some data suggesting that patients with bulky adenopathy do not have as sustained a PFS with ibrutinib. In the study of BGB-3111, the lymph nodes had a sustained occupancy above 90% at doses of 160 twice daily or 320 daily.

The interim analysis provided data for 46 of 63 CLL/SLL patients. The most common side effects with BGB-3111 were petechiae, purpura, and contusion, suggesting that the low IC50 for TEC may lead to minor bleeding, similar to that seen with ibrutinib. Diarrhea, however, was much less frequent than with ibrutinib, occurring in only 20% of patients. There was 1 episode of serious hemorrhage, and 1 episode of atrial fibrillation. The response rate was 96%, which is quite good, especially considering that the patients in the study had relapsed/refractory disease. These patients also showed improvements in cytopenias. Among the relapsed/refractory patients, the median number of prior regimens was 2, so they were less heavily pretreated than patients in the ibrutinib trials previously discussed. No patient has yet developed progressive disease, and there have been no reports of Richter’s transformation. These data are encouraging.

Idelalisib in Combination With Bendamustine and Rituximab

Dr Andrew Zelenetz presented an updated analysis of overall survival in a randomized, placebo-controlled, phase 3 trial of idelalisib added to bendamustine and rituximab (BR) in patients with relapsed/refractory CLL.8 Previous data for this study were presented at the 2015 ASH meeting.9 The new analysis is based on a longer median follow-up of 21 months. This study shows a survival benefit when idelalisib is added to bendamustine and rituximab. Median overall survival was 40.6 months in the placebo arm—patients who received BR without idelalisib—and was not reached in the idelalisib plus BR arm. The difference was statistically significant. This survival advantage is a new finding. The PFS continues to be very different, at a median of 11 months with placebo vs 23 months with idelalisib. This improvement was seen in basically all subgroups. An analysis that removed the patients with 17p or TP53 mutation showed that the median PFS did not change in the placebo arm, but increased to up to 28 months in the idelalisib arm.

In terms of AEs, more febrile neutropenia was seen with idelalisib than placebo. In the idelalisib group, 24% of patients experienced grade 3 or higher febrile neutropenia, vs only 6% in the placebo group. There was more transaminitis in the idelalisib arm, as is seen in single-agent use. There was also more pneumonia among patients who received idelalisib, at 17% vs 8%. Four cases of Pneumocystis jirovecii pneumonia (PJP) occurred in the idelalisib plus BR arm, vs none in the placebo/BR arm. There were 13 cases of cytomegalovirus (CMV) in the idelalisib plus BR arm and only 3 in the placebo plus BR arm. In March 2016, the FDA closed the frontline trials of idelalisib based on a higher incidence of infection. Most of that patient population received BR plus idelalisib as initial therapy. Thus, it was the same regimen in the frontline setting that led to the closing of the frontline studies. Similarly, in the current analysis, there were more cases of PJP and CMV, but the majority of the infections were not atypical. In addition, despite these infections, there was still a significant survival advantage in favor of the idela-lisib/BR arm.

Disclosure

Dr O’Brien is a consultant for Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc, Vaniam Group LLC, AbbVie, Sunesis, and Alexion. She has received research support from ProNAi, Regeneron, and Acerta. She is a consultant and/or has received research support from Gilead, Pharmacyclics, TG Therapeutics, and Pfizer.